Estrogens, and in particular E2, have been used for decades for treating estrogen deficiency symptoms, i.e. vasomotor symptoms. Hot flushes are the most common and bothersome clinical symptom of menopause, affecting approximately 75% of postmenopausal women (Sterns et al. Lancet 2002; 360; 1851-1861). Other menopausal symptoms include mood changes, urogenital changes, sexual dysfunction, and skin changes. The increase in occurrence of hot flushes is linked with the reduction of the endogenous estrogen level that goes along with menopause. Menopausal symptoms cause discomfort and distress, ranging from tolerable to, at times, severe enough to affect a woman's quality of life. Also, the loss of endogenous estrogen during menopause accelerates the risk for chronic diseases, such as osteoporosis (Slemenda et al. Epidemiology of Osteoporisis. In: Treatment of the Postmenopausal Woman Basic and Clinical Aspects. Raven Press. New York. 1994, p. 161-168). Currently, there are more than 40 million menopausal women in the United States and almost half of them are above the age of 63 (Warren et al. Clin Obstet Gynecol 2004; 47(2);450-470). As life expectancy continues to increase, most women will spend one-third of their lifetime in postmenopause.
Although E2 doses are adjusted during therapy according to individual responses, it is, needless to say, of importance to establish the lowest E2 dose that confidentially can be used to initiate or maintain therapy.
Important factors, which are relevant in identifying the lowest initial dose of E2, include rapid and adequate release of vasomotor symptoms, and appropriateness for most women. Besides being effective, the initial dose or the maintenance dose should be well tolerated.
Notelovitz et al. (Obstet Gynecol 2000; 95(5);726-731) evaluated a range of E2 doses for symptom relief in menopausal women who needed treatment for moderate and severe vasomotor symptoms, and used the collected data to identify the ideal lowest initial dose. More particular, Notelovitz et al. conducted a randomized, double-masked, placebo-controlled 12-week study in which 333 menopausal women with moderate or severe but flushes were assigned to treatment with 0.25 mg E2, 0.5 mg E2, 1 mg E2, 2 mg E2, or placebo (administered orally). The number and severity of hot flushes were recorded on a daily basis.
Notelovitz et al. found a significant linear dose-response relationship between the E2 dose and reduction in vasomotor symptoms, assessed by the number of moderate to severe hot flushes and the hot flush weekly weighted score. At the end of the 12-week treatment period, decreases in the number of hot flushes and the hot flush weekly weighted score were significantly greater in the 0.5-, 1-, and 2-mg groups compared with the placebo group. However, at week 4 only the 1- and 2-mg groups showed significance compared to the placebo group.
Accordingly, Notelovitz et al. concluded that 1 mg E2 is the most useful starting dose for treating moderate to severe menopausal symptoms in menopausal women. According to Notelovitz et al. lower doses either require more time (0.5 mg E2) or are ineffective (0.25 mg E2) for symptom relief in women who suffer from moderate to severe vasomotor symptoms. Conversely, a higher dose of 2 mg E2 is effective for symptom relief, but is associated with increased estrogen-related adverse events.
Nevertheless, and as also emphasized by the Women's Health Initiative (WHI), there is still a need for developing and investigating dosage forms having lower doses of E2 for the treatment of vasomotor symptoms. In particular, there is a need for developing dosage forms having lower doses of E2 for the treatment of vasomotor symptoms, which have a fast and reliable onset, and hence are suitable to be used already when hormone replacement therapy is initiated, thereby avoiding initial treatment with dosage forms containing higher doses of E2.
This is also emphasised in the FDA guidelines where sponsors are encouraged to investigate dosing schedules and drug delivery systems that can achieve efficacy with the lowest possible exposures (Guidance for Industry: Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Recommendations for Clinical Evaluation; U.S. Department of Health and Human Services; Food and Drug Administration; CDER; January 2003).
Dosage forms comprising a combination of E2 and DRSP have been described in WO 01/52857. While low-dose E2 dosage forms are formally encompassed by the disclosure in WO 01/52857, the preferred E2 dose described therein is 1 mg.
Low-dose E2-only dosage forms are described in WO 2006/048261.
An HRT product, Angeliq®, which contains 1 mg E2 and 0.5 mg DRSP, has been approved and marketed in the US.